Alcaraz, Lilian (Loughborough, GB)
Furber, Mark (Loughborough, GB)
Mortimore, Michael (Oxfordshire, GB)
Pimm, Austen (Loughborough, GB)
Thorne, Philip (Loughborough, GB)
Willis, Paul (Loughborough, GB)

10/813426

11/07/2006

03/31/2004

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AstraZeneca AB (Sodertalje, SE)

514/620

564/164, 514/623, 564/188

C07C233/35; A61K31/165; A61K31/166; C07C237/30

564/188, 564/183, 514/620, 514/617, 564/164, 514/623

6242470	Adamantane derivatives	June, 2001	Baxter et al.
6258838	Compounds	July, 2001	Baxter et al.
6303659	Compounds	October, 2001	Baxter et al.
6492355	Adamantane derivatives	December, 2002	Alcaraz et al.
6555541	Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions	April, 2003	Furber et al.
6881754	Adamantane derivatives	April, 2005	Alcaraz et al.	514/617

EP0074768	March, 1983			Alkanoylanilides.
EP0395093	October, 1990			Triphenylmethane derivatives.
EP0564924	October, 1993			2-Oxoethyl derivatives as immunosuppressants.
EP0582164	February, 1994			Adenosine re-uptake inhibiting derivatives of diphenyl oxazoles, thiazoles and imidazoles.
FR2346011	October, 1977
WO/1995/004720	February, 1995			GASTRIN AND CCK RECEPTOR LIGANDS
WO/1995/030647	November, 1995			CCK AND GASTRIN RECEPTOR LIGANDS
WO/1995/032949	December, 1995			GASTRIN AND CCK ANTAGONISTS
WO/1996/013262	May, 1996			MUSCARINE ANTAGONISTS
WO/1997/032882	September, 1997			PYRIMIDOPYRIMIDINES, MEDICAMENTS CONTAINING THESE COMPOUNDS, THEIR USE AND PROCESS FOR THEIR PRODUCTION
WO/1999/031096	June, 1999			PIPERAZINE DERIVATIVES USEFUL AS HYPOGLYCEMIC AGENTS
WO/1999/029686	July, 1999			NOVEL COMPOUNDS
WO/1999/059582	November, 1999			AMIDE THERAPEUTICS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE
WO/2000/061569	October, 2000			ADAMANTANE DERIVATIVES
WO/2000/071529	November, 2000			SUBSTITUTED PHENYL COMPOUNDS WITH IMMUNOSUPPRESSING ACTIVITY AND PHARMACEUTICAL COMPOSITIONS
WO/2001/042194	June, 2001			ADAMANTANE DERIVATIVES
WO/2001/044213	June, 2001			NEW P2X�7? RECEPTOR ANTAGONISTS FOR USE IN THE TREATMENT OF INFLAMMATORY, IMMUNE OR CARDIOVASCULAR DISEASES
WO/2001/046200	June, 2001			NOVEL PIPERIDINE AND PIPERAZINE DERIVATIVES

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Saeed, Kamal A.

Nolan, Jason M.

Morgan Lewis & Bockius LLP

This is a Continuation of application Ser. No. 10/149,549, filed Jun. 16, 2002 now U.S. Pat. No. 6,881,754, which is a PCT National Stage of PCT/SE00/02505 filed Dec. 12, 2000.

The invention claimed is:

1. A compound of general formula wherein D represents CH₂ or CH₂CH₂; E represents C(O)NH or NHC(O); R¹ and R² each independently represent hydrogen, halogen, amino, nitro, C₁–C₆ alkyl or trifluoromethyl, but R¹ and R² may not both simultaneously represent hydrogen; R³ represents a group of formula R⁴ represents a C₁–C₆ alkyl group; X represents a group NR¹³; R⁵ hydrogen; and R¹³ represents hydrogen, C₃–C₈ cycloalkyl, C₃–C₈ cycloalkylmethyl, or R¹³ represents a C₁–C₆ alkyl group optionally substituted by at least one substituent selected from hydroxyl and C₁–C₆ alkoxy; with the proviso that when E is C(O)NH, X is not NH or N(C₁–C₆ alkyl); or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein D represents CH₂.

3. A compound according to claim 1, wherein E represents NHC(O).

4. A compound according to claim 1, wherein R¹ and R² each independently represent a hydrogen, chlorine or bromine atom, or an amino, nitro, C₁–C₃ alkyl or trifluoromethyl group.

5. A compound according to claim 1, wherein X represents a group NR¹³ in which R¹³ represents hydrogen, —(CH₂)₂OH, methyl, ethyl,n-propyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclohexylmethyl.

6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is selected from: 2-Chloro-5-[(3-hydroxy-2,2-dimethylpropylamino)methyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[(5-hydroxypentylamino)methyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, acetate salt, 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 2-Chloro-5-[3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, acetate salt, 2-Chloro-5-[(3-[(1 -methylethyl)amino]propyl]-N-(tricyclo [3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 2-Chloro-5-[3-[(4-hydroxybutyl)amino]propyl]-N-(tricyclo [3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(2-hydroxy-2-methylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, acetate salt, (S)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, (R)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, (R)-2-Chloro-5-[3-[(2-hydroxy-1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 2-Chloro-5-[3-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(3-methoxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 2-Chloro-5-[3-[(3-hydroxy-3-methylbutyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 2-Chloro-5-[3-[(2-methoxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt, 5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)benzamide, 2-Chloro-5-[3-(cyclohexylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[[1-(hydroxymethyl)-2,2-dimethylpropyl]amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-(cyclopropylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(1,1-dimethylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-(cyclopentylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-5-[3-[(1,2,2-trimethylpropyl)amino]propyl]-benzamide, 5-[3-(Butylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[[1-(hydroxymethyl)-2-methylpropyl]amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(1-methylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-](2-hydroxy-1,1-dimethylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, 2-Chloro-5-[3-[(cyclohexylmethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide, and 2-Chloro-5-[3-[(2-methoxy-1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

7. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises: (a) reacting a compound of general formula wherein L¹ represents a leaving group and D, E, R¹, R² and R⁴ are as defined in formula (I), with a compound of general formula wherein R⁵ and R¹³ are as defined in formula (I), optionally in the presence of a suitable silver salt; or (b) reacting a compound of general formula wherein R²⁰ represents a bond or C₁–C₅ alkyl group and D, E, R¹ and R² are as defined in formula (I), with a compound of general formula (VI) as defined in (a) above, in the presence of a reducing agent; and optionally after (a) or (b) converting the compound of formula (I) obtained to a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1–4, 5 and 6 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1–4, 5 and 6 with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A method of treating rheumatoid arthritis which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1–4, 5 and 6 to a patient in need thereof.

11. A method of treating chronic obstructive pulmonary disease which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1–4, 5 and 6 to a patient in need thereof.

12. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

13. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

14. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-(methylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

15. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

16. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-[(2-hydroxy-2-methylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

17. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)benzamide.

18. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-(cyclohexylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

19. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-(cyclopropylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

20. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-(cyclopentylamino)propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

21. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 which is: 2-Chloro-5-[3-[(cyclohexylmethyl)amino]propyl]-N-(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)-benzamide.

The present invention relates to adamantane derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.

The P2X ₇ receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X ₇ receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1β (IL-1β) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X ₇ receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones and renal mesangial cells.

It would be desirable to make compounds effective as P2X ₇ receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X ₇ receptor may play a role.

In accordance with the present invention, there is therefore provided a compound of general formula

wherein D represents CH ₂ or CH ₂ CH ₂ , preferably CH ₂ ;

• E represents C(O)NH or, preferably, NHC(O);
• R ¹ and R ² each independently represent hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), amino (NH ₂ ), nitro (NO ₂ ), C ₁ –C ₆ alkyl or trifluoromethyl, but R ¹ and R ² may not both simultaneously represent hydrogen;
• R ³ represents a group of formula

• R ⁴ represents a C ₁ –C ₆ alkyl group;
• X represents an oxygen or sulphur atom or a group NR ¹³ , SO or SO ₂ ;
• R ⁵ represents hydrogen, or R ⁵ represents C ₁ –C ₆ alkyl or C ₂ –C ₆ alkenyl, each of which may be optionally substituted by at least one substituent selected from halogen, hydroxyl, (di)-C ₁ –C ₆ -alkylamino, —Y—R ⁶ ,

and
a 5- or 6-membered heteroaromatic ring comprising from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur which heteroaromatic ring may itself be optionally substituted by at least one substituent selected from halogen, hydroxyl and C ₁ –C ₆ alkyl;

• Y represents an oxygen or sulphur atom or a group NH, SO or SO ₂ ;
• R ⁶ represents a group —R ⁷ Z where R ⁷ represents a C ₂ –C ₆ alkyl group and Z represents an —OH, —CO ₂ H, —NR ⁸ R ⁹ , —C(O)NR ¹⁰ R ¹¹ or —N(R ¹² )C(O)—C ₁ –C ₆ alkyl group, and, in the case where Y represents an oxygen or sulphur atom or a group NH, R ⁶ additionally represents hydrogen, C ₁ –C ₆ alkyl, C ₁ –C ₆ alkylcarbonyl, C ₁ –C ₆ alkooxycarbonyl, —C(O)NR ¹⁴ R ¹⁵ , —CH ₂ OC(O)R ¹⁶ , —CH ₂ OC(O)OR ¹⁷ or —C(O)OCH ₂ OR ¹⁸ ;
• R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom or a C ₁ –C ₆ alkyl group;
• R ¹³ represents hydrogen, C ₃ –C ₈ cycloalkyl, C ₃ –C ₈ cycloalkylmethyl, or R ¹³ represents a C ₁ –C ₆ alkyl group optionally substituted by at least one substituent selected from hydroxyl and C ₁ –C ₆ alkoxy; and
• R ¹⁴ , R ¹⁵ R ¹⁶ , R ¹⁷ and R ¹⁸ each independently represent a C ₁ –C ₆ alkyl group;
• with the proviso that when E is C(O)NH, X is O, NH or N(C ₁ –C ₆ alkyl), then R ⁵ is other than a hydrogen atom or an unsubstituted C ₁ –C ₆ alkyl group;
• or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group maybe linear or branched. In the present invention, an alkyl group or moiety may contain up to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl. A C ₂ –C ₆ alkenyl group may be linear or branched. In a di-C ₁ –C ₆ -alkylamino group, the alkyl moieties may be the same or different.

In one embodiment of the invention, when E represents C(O)NH, then X is S, SO or SO ₂ .

In another embodiment of the invention, when E represents NHC(O), then X is O or NR ¹³ .

Preferably, R ¹ and R ² each independently represent a hydrogen or halogen atom, or an amino, nitro, C ₁ –C ₄ alkyl or trifluoromethyl group (but R ¹ and R ² may not both simultaneously represent a hydrogen atom).

More preferably, R ¹ and R ² each independently represent a hydrogen, chlorine or bromine atom, or an amino, nitro, C ₁ –C ₃ alkyl or trifluoromethyl group (but R ¹ and R ² may not both simultaneously represent a hydrogen atom).

Most preferably, R ¹ and R ² each independently represent a hydrogen or chlorine atom (but R ¹ and R ² may not both simultaneously represent a hydrogen atom).

R ⁴ represents a C ₁ –C ₆ alkyl group, for example a linear C ₁ –C ₆ alkyl group such as CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ or (CH ₂ ) ₄ .

Preferably X represents an oxygen atom or, especially, a group NR ¹³ .

R ⁵ represents hydrogen, or R ⁵ represents C ₁ –C ₆ alkyl or C ₂ –C ₆ alkenyl (e.g. ethenyl or —CH ₂ CH═CH ₂ ), each of which may be optionally substituted by at least one substituent, e.g. one, two or three substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, (di)-C ₁ –C ₆ -alkylamino (e.g. methylamino, ethylamino, dimethylamino or diethylamino), —Y—R ⁶ ,

and
a 5- or 6-membered heteroaromatic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur which heteroaromatic ring may itself be optionally substituted by at least one substituent, e.g. one or two substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C ₁ –C ₆ , preferably C ₁ –C ₄ , alkyl, e.g., imidazolyl (such as imidazol-1-yl or imidazol-4-yl), 1-methylimidazolyl (such as 1-methylimidazol-4-yl), 2,3,5-triazolyl and 2,3,4,5-tetrazolyl.

Preferred compounds are those in which R ⁵ represents an optionally substituted C ₁ –C ₆ alkyl group. A preferred optional substituent is —Y—R ⁶ .

When Y represents SO or SO ₂ , R ⁶ represents a group —R ⁷ Z where R ⁷ represents a C ₂ –C ₆ alkyl group and Z represents an —OH, —CO ₂ H, —NR ⁸ R ⁹ , —C(O)NR ¹⁰ R ¹¹ or —N(R ¹² )C(O)—C ₁ –C ₆ alkyl group.

When Y represents an oxygen or sulphur atom or a group NH, R ⁶ may represent a group —R ⁷ Z as defined above (particularly —(CH ₂ ) ₂ OH or —(CH ₂ ) ₃ OH), or R ⁶ may represent hydrogen, C ₁ –C ₆ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or t-butyl), C ₁ –C ₆ alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl or t-butylcarbonyl), C ₁ –C ₆ alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or t-butoxycarbonyl), —C(O)NR ¹⁴ R ¹⁵ , —CH ₂ OC(O)R ¹⁶ , —CH ₂ OC(O)OR ¹⁷ or —C(O)OCH ₂ OR ¹⁸ .

Y is preferably an oxygen or sulphur atom or a group NH.

In one embodiment of the invention, Y represents an oxygen of sulphur atom or a group NH and R ⁶ represents —(CH ₂ ) ₂ OH, —(CH ₂ ) ₃ OH, hydrogen, methyl, isopropyl, methylcarbonyl or t-butylcarbonyl. In another embodiment, Y represents oxygen and R ⁶ represents hydrogen.

Preferably R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² each independently represent a hydrogen atom is or a C ₁ –C ₄ alkyl group.

R ¹³ represents hydrogen, C ₃ –C ₈ , preferably C ₃ –C ₆ , cycloalkyl C ₃ –C ₈ , preferably C ₃ –C ₆ , cycloalkylmethyl, or R ¹³ represents a C ₁ –C ₆ alkyl group optionally substituted by at least one substituent, e.g. one, two or three substituents independently selected from hydroxyl and C ₁ –C ₆ alkoxy. Examples of preferred groups R ¹³ include hydrogen, —(CH ₂ ) ₂ OH, methyl, ethyl, n-propyl, isopropyl, n-butyl; n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl and cyclohexylmethyl.

• R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ each independently represent a C ₁ –C ₆ , or C ₁ –C ₄ , alkyl group.

Preferred compounds of the invention include:

2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[[2-(2-hydroxyethoxy)ethylamino]methyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[(3-hydroxy-2,2-dimethylpropylamino)methyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[(5-hydroxypentylamino)methyl]-N-(tricyclo[3 3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[[2-[(2-hydroxyethylthio)ethylamimo]methyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(methylamino)propyl]-N-(tricyclo(3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3 .3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[3-[(2-Amino-2-methylpropyl)amino]propyl]-2-chloro-N-(t ricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(4-hydroxybutyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxy-2-methylpropyl)amino]propyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(methylamino)ethyl]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt,

(S)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tric yclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt,

(R)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tric ylo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

(R)-2-Chloro-5-[3-[(2-hydroxy-1-methylethyl)amino]propyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt,

2-Chloro-5-[3-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl ]amino]propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[3-[[2-(Acetylamino)ethyl]amino]propyl]-2-chloro-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt,

2-Chloro-5-[3-[[2-(diethylamino)ethyl]amino]propyl]-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochoride salt,

2-Chloro-5-[3-[(3-methoxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt,

2-Chloro-5-[3-[(3-hydroxy-3-methylbutyl)amino]propyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, hydrochloride salt,

2-Chloro-5-[3-[(2-methoxyethyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 dec-1-ylmethyl)benzamide, hydrochloride salt,

2-Chloro-5-[[3-(methylamino)proproxy]methyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl) benzamide,

2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(t ricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt,

2-Chloro-5-[[2-[(3-hydroxypropyl)amino]ethoxy]methyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt,

2-Chloro-5-[[[3-[(1-methylethyl)amino]propyl]amino]methyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

5-[[(3-Aminopropyl)amino]methyl]-2-chloro-N-(tricyclo(3.3 .1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[[[2-[(1-methylethyl)amino]ethyl]amino]methyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]-carbonyl]phenyl]propyl]amino]pr opanoic acid, 2,2-dimethylpropyl ester, trifluoroacetic acid salt,

5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

2-Chloro-5-[3-[(2-hydroxyethyl)pentylamino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(methyl-2-propenylamino)propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(dimethylamino)ethyl]methylamino]propyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[3-(Butylethylamino)propyl]-2-chloro-N-(tricyclo[3.3.1. 1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(methylpentylamino)propyl]-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(diethylamino)ethyl]ethylamino]propyl]- N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxyethyl)methylamino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(dipropylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxyethyl)(1-methylethyl)amino]propy l]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[3-[Butyl(2-hydroxyethyl)amino]propyl]-2-chloro-N-(tric yclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(diethylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(dimethylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[3-(Butylmethylamino)propyl]-2-chloro-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxyethyl)propylamino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[ethyl(2-hydroxyethyl)amino]propyl]-N-(tric yclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(dibutylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(ethylpropylamino)propyl]-N-(tricyclo(3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[methyl(1-methylethyl)amino]propyl]-N-(tric yclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

2-Chloro-5-[3-[[3-(dimethylamino)propyl]methylamino]propy l]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(cyclohexyl(2-hydroxyethyl)amino]propyl]-N -(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(cyclohexylmethylamino)propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(cyclohexylamino)propyl]-N-(tricyclo[3.3.1. 1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[1-(hydroxymethyl)-2,2-dimethylpropyl]amin o]propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(cyclopropylamino)propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(dimethylamino)ethyl]amino]propyl]-N-(t ricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(1,1-dimethylethyl)amino]propyl]-N-(tricyc lo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[3-(dimethylamino)propyl]amino]propyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(cyclopentylamino)propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-5-[3-[(1,2,2-trimethylpropyl)amino]pr opyl]-benzamide,

5-[3-(Butylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[1-(hydroxymethyl)-2-methylpropyl]amino]pr opyl]-N-(tricyclo[3.3.1.1 ^3.7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(1-methylpropyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(methylthio)ethyl]amino]propyl]-N-(tric yclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-hydroxy-1,1-dimethylethyl)amino]propyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(cyclohexylmethyl)amino]propyl]-N-(tricycl o[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-(2-propenylamino)propyl]-N-(tricyclo[3.3.1. 1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-fluoroethyl)amino]propyl]-N-(tricyclo[3 .3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[(2-methoxy-1-methylethyl)amino]propyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, dihydrochloride salt,

5-[[[(1-Aminocyclopropyl)methyl](2-hydroxyethyl)amino]met hyl]-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

5-[[(2-Hydroxyethyl)[2-(methylamino)ethyl]amino]methyl]-2 -methyl-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide,

2-Chloro-5-[3-[[2-(ylmethyl-1H-imidazol-4-yl)ethyl]amino] propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

2-Chloro-5-[3-[[2-(1H-imidazol-4yl)ethyl]amino]propyl]-N- (tricyclo[3.3.1.1. ^3,7 ]dec-1-ylmethyl)benzamide,

2-Chloro-5-[3-[[3-(1H-imidazol-1-yl)propyl]amino]propyl]- N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide,

and pharmaceutically acceptable salts and solvates thereof.

The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:

• (a) when X represents an oxygen or sulphur atom or a group NR ¹³ , reacting a compound of general formula

wherein L ¹ represents a leaving group (e.g, a halogen atom or trifluoromethanesulphonate group) and D, E, R ¹ , R ² and R ⁴ are as defined in formula (I), with a compound of general formula

wherein X′ represents an oxygen or sulphur atom or a group NR ¹³ , and R ⁵ is as defined in formula (I), optionally in the presence of a suitable silver salt (e.g. silver trifluoromethamelphonate); or

• (b) when X represents SO or SO ₂ , reacting a corresponding compound of formula (I) in which X represents a sulphur atom with a suitable oxidising agent; or
• (c) when X represents a group NR ¹³ , reacting a compound of general formula

wherein R ²⁰ represents a bond or C ₁ –C ₅ alkyl group and D, E, R ¹ and R ² are as defined in formula (I), with a compound of general formula

wherein R ⁵ and R ¹³ are as defined in formula (I), in the presence of a reducing agent (e.g. sodium triacetoxyborohydride);

and optionally after (a), (b) or (c) converting thy compound of formula (I) obtained to a pharmaceutically acceptable salt or solvate thereof.

The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, 1,2-dichloroethane or tetrahydrofuran, at a temperature, e.g. in the range from 0 to 200° C., preferably in the range from 0 to 150° C. The oxidising agent used in (b) above may, for example, be 3-chloroperoxybenzoic acid or potassium peroxymonosulphate, commercially sold under the trade mark “OXONE”.

Compounds of formula (V) in which R ²⁰ represents a bond may be prepared by reacting a compound of general formula

wherein Hal represents a halogen atom such as bromine and D, E, R ¹ and R ² are as defined in formula (I), with a base such as t-butyllithium and then with a formylating agent such as dimethylformamide.

Compounds of formula (VII) may conveniently be prepared by reacting a compound of general formula

wherein R ²⁵ represents NH ₂ or CO ₂ H and D is as defined in formula (I), with a compound of general formula

wherein R ³⁰ represents CO ₂ H or NH ₂ , and R ¹ , R ² and Hal are as defined in formula (VII) above.

Compounds of formula (V) in which R ²⁰ represents a C ₁ –C ₅ alkyl group may be prepared, for example, by reacting a corresponding compound of formula (V) in which R ²⁰ represents a bond with (methoxymethyl)diphenylphosphineoxide in the presence of a base, or, with a compound of general formula

in which n is 0, 1, 2 or 3 and R and R′ independently represent C ₁ –C ₆ alkyl groups, followed by hydrogenation.

Alternatively, compounds of formula (V) in which R ²⁰ represents a C ₂ –C ₅ alkyl group may be prepared by reacting a compound of formula (VII) with an alkenol (e.g. 2-propen-1-ol (allyl alcohol), but-3-enol, pent-4enol or hex-5-enol) in the presence of a palladium catalyst, optionally followed by a hydrogenation reaction and an oxidation reaction using, for example, Dess-Martine periodinane reagent (these last two steps are not required when the alkenol is allyl alcohol).

As a further alternative, compounds of formula (V) in which R ²⁰ represents a C ₂ –C ₅ alkyl group may be prepared by reacting a compound of formula (VII) with an alkenoate ester (e.g. methyl acrylate or ethyl acrylate) in the presence of a palladium catalyst such as palladium acetate, followed by reduction of the ester group to a hydroxyl group and then oxidation to the aldehyde with an oxidising agent (e.g. Dess-Martin periodinane reagent).

Compounds of formula (I) in which R ⁵ represents a C ₂ –C ₆ alkyl group substituted by a group —Y—R ⁶ where Y represents O, S or NH and R ⁶ represents a group —R ⁷ Z as defined above, may be prepared by reacting a corresponding compound of formula (I) in which R ⁵ represents a C ₂ –C ₆ alkyl group substituted by a hydroxyl group with a hydroxyl activating agent (such as methanesulphonyl chloride) in the presence of a base (such as triethylamine), followed by reaction with a compound of formula HO—R ⁷ Z, HS—R ⁷ Z or H ₂ N—R ⁷ Z.

Compounds of formula (I) wherein E represents a group NHC(O) may be prepared from a compound of general formula

wherein R ¹ , R ² and R ³ are as defined in formula (I) and X represents O, S or NR ¹³ , by reaction with adamantylmethylamine or adamantylethylamine, in the presence of a coupling agent such as 1,1′-carbonyldiimidazole.

Compounds of formula (I) wherein E represents a group C(O)NH may be prepared from a compound of general formula

wherein R ¹ , R ² and R ³ are as defined in formula (I) and X represents O, S or NR ¹³ , by reaction with adamantylacetyl chloride or adamantylpropanoyl chloride in the presence of a base such as triethylamine.

Compounds of formula (XI) can be prepared from a compound of general formula

wherein L ² represents a leaving group (such as a halogen atom or trifluoromethanesulphonate group) and R ¹ , R ² and R ⁴ are as defined in formula (I), with a compound of formula (IV) as defined above, optionally in the presence of a silver salt such as silver trifluoromethanesulphonate.

Compounds of formula (XII) can be prepared from a compound of general formula

wherein L ³ represents a leaving group (such as a halogen atom or trifluoromethanesulphonate group) and R ¹ , R ² and R ⁴ are as defined in formula (I), with a compound of formula (IV) as defined above, optionally in the presence of a silver salt such as silver trifluoromethanesulphonate.

It will be appreciated that certain compounds of formula (I) may be converted into further compounds of formula (I). For example, compounds of formula (I) in which —Y—R ⁶ represents —OH can be converted to compounds in which Y is O and R ⁶ is C ₁ –C ₆ alkoxycarbonyl, by reaction with an acylating agent. Furthermore, compounds of formula (I) in which X represents NR ¹³ and R ¹³ is other than hydrogen, for example, a cyclohexyl group can be prepared by reacting a compound of formula (I) in which X represents NH with cyclohexanone in the presence of a reducing agent such as sodium triacetoxyborohydride.

Compounds of formula (III), (IV), (VI), (VIII), (IX), (X), (XIII) and (XIV) as well as compounds HO—R ⁷ Z, HS—R ⁷ Z and H ₂ N—R ⁷ Z are either commercially available, are well known in the literature or may be prepared easily using known techniques.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl, carboxyl, aldehyde, carbonyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve at a certain stage the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, furnarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

The compounds of the present invention are advantageous in that they possess pharmacological activity and have utility as modulators of P2X ₇ receptor activity. They are therefore indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, neurodegenerative disease, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke, peripheral vascular disease and varicose veins.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary The terms “therapeutic” and “therapeutically” should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis, psoriasis, pulmonary disease, e.g. COPD or bronchitis, or diseases of the central nervous system, e.g. Alzheimer's disease or stroke) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disease or condition indicated. For effecting immunosuppression, the daily dosage of the compound of formula (I) will typically be in the range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably frorm 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.

Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

The present invention will now be further explained by reference to the following illustrative examples.

EXAMPLE 1

2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide dihydrochloride.

a) 5-Bromo-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

To a suspension of 5-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and DMF (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloroethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 hs. The reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound as a solid (7.84 g).

MS (APCI+ve) 382/384/386 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.42 (1H, t); 7.63 (1H, dd); 7.57 (1H, m); 7.45 (1H, d), 2.93 (2H, d); 1.94 (3H, s, br); 1.69–1.58 (6H, m); 1.51 (6H, s).

b) 2-Chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (3.25 g, Example 1a) in tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of 1.4M methyllithium in diethyl ether (6.1 ml) was added to this solution over 2 min. The mixture was stirred at −78° C. for 10 min, then a 1.7M solution of tert-butyllithium in pentane (10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min., then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min., quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitled compound as a solid (2.76 g).

MS (APCI+ve) 332/334 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 10.04 (1H, s); 8.49 (1H, t); 7.96–7.91 (2H, m); 7.74 (1H, d); 2.96 (2H, d), 1.95 (3H, s); 1.64 (6H, m); 1.53 (6H, d).

c) 2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide dihydrochloride

A mixture of 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.244 g, Example 1b), 2-(2-aminoethylamino)-ethanol (0.154 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 hs, cooled and concentrated under reduced pressure to give an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.030 g) was added portionwise to this and the mixture stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue purified by column chromatography over silica gel (eluting with 7:3:0.3 dichloromethane/methanol/35% aqueous ammonia) to give the free base. This was dissolved in methanol (10 ml) and treated with 4M hydrochloric acid in dioxane (4 ml) to give a solid precipitate. This was filtered off and washed with diethyl ether to afford the title compound as a solid (0.165 g).

MS (APCI+-ve) 420/422 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.36 (1H, t); 7.61–7.57 (3H, m); 5.31 (1H s, br); 4.22 (2H, s, br); 3.63 (2H, s, br); 3.05 (2H, s, br); 2.95 (2H, 4); 1.95 (3H, s, br); 1.69–1.59 (6H, m); 1.53 (6H, s, br).

EXAMPLE 2

2-Chloro-5-[[2-(2-hydroxyethoxy)ethylamino]methyl]-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

To a solution of 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.150 g, Example 1b) and 2-(2-aminoethoxy)ethanol (0.065 ml) in 1,2-dichloroethane (6 ml) was added sodium triacetoxyborohydride (0.134 g), and the mixture was stirred overnight at room temperature. Water (20 ml) and dichloromethane (20 ml) were added and the layers were partitioned. The organics were washed with brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0–10% ethanol in dichloromethane to give the title compound as a white powder (0.016 g).

MS (APCI+ve) 421/423 (M+H) ³⁰

¹ H NMR (DMSO-d ₆ ) δ 8.29 (1H, s, br); 7.42–7.34 (3H, m); 4.60 (1H, s, br); 3.71 (2H, s); 3.47 (4H, s); 3.40 (2H, d); 2.93 (2H, d); 2.63 (2H, d); 1.94 (3H, s); 1.64 (6H, q); 1.52 (6H, s).

EXAMPLE 3

2-Chloro-5-[(3-hydroxy-2,2-dimethylpropylamino)methyl]-N -(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.150 g, Example 1b), 3-amino-2,2-dimethylpropanol (0.093 g) and sodium triacetoxyborohydride (0.134 g) in 1,2-dichloroethane (6 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0–10% ethanol in dichlorometane to give the title compound as a white powder (0.035 g).

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.29 (1H, t); 7.41–7.34 (3H, m); 4.60 (1H, s, br); 3.70 (2H, s); 3.16 (2H, s); 2.93 (2H, d); 2.29 (2H, s); 1.94 (3H, s, br); 1.63 (6H, q); 1.52 (6H, d); 0.80 (6H, s).

EXAMPLE 4

2-Chloro-5-[(5-hydroxypentylamino)methyl]-N-(tricyclo[3. 3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

A mixture of 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.100 g, Example 1b), 5-amino-1-pentanol (0.031 mg) and titanium(IV) isopropoxide (0.111 ml) was stirred under nitrogen for 1 h at room temperature. The viscous solution obtained was diluted with absolute ethanol (2 ml). Sodium cyanoborohydride (0.013 g) was added, and the solution was stirred for 20 h at room temperature. Water (5 ml) was added with stirring and the resulting precipitate was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane (20 ml) and filtered to remove the remaining inorganic residues. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0–10% ethanol in dichloromethane to give the title compound as a white powder (0.031 g).

MS (APCI+ve) 419/421 (M) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.28 (1H, t); 7.41–7.34 (3H, m); 5.30 (1H, s); 4.31 (1H, t); 3.67 (2H, s); 3.37–3.32 (2H, m); 2.93 (2H, d); 2.46–2.42 (2H, m); 1.94 (3H, s); 1.63 (6H, q); 1.52 (6H, s); 1.43–1.36 (2H, m); 1.32–1.28 (2H, m); 1.27–1.21 (2H, m).

EXAMPLE 5

2-Chloro-5-[[2-(2-hydroxyethylthio)ethylamino]methyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.800 g, Example 1b), 2-(2-aminoethylthio)ethanol (0.584 g) and sodium triacetoxyborohydride (0.715 g) in 1,2-dichloroethane (15 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0–10% ethanol in dichloromethane to give the title compound as a white powder (0.536 g).

MS (APCI+ve) 437/439 (M)+

1H NM (DMSO-d ₆ ) δ 8.29 (1H, t); 7.42–7.35 (3H, m); 4.78 (1H, s, br); 3.71 (2H, s); 3.50 (2H, t); 2.93 (2H, d); 2.68–2.58 (4H, m); 2.56–2.52 (2H, m); 1.94 (3H, s, br); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 6

2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo [3.1.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetate salt

a) (2E)-3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-2-propenoic acid, methyl ester

5-Bromo-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (5 g), methyl acrylate (1.4 ml), triethylamine (2.1 ml), palladium acetate (0.070 g) and tri-orthotolyl phosphine (0.185 g) were combined in N,N-dimethylformamide (20 ml). The mixture was heated in a sealed tube under nitrogen at 90° C. for 24 h. After cooling, the reaction mixture was partitioned between dichloromethane and dilute hydrochloric acid, the mixed phases were filtered through celite and the phases separated. The organic layer was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue which was triturated with diethyl ether and filtered to yield the subtitled compound as an off white solid (4.1 g).

MS (APCI+ve) 388/390 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.84 (1H, d); 7.64 (1H, d); 7.49 (1H, dd); 7.43 (1H, d); 6.45 (1H, d); 6.24 (1H, t, br); 3.81 (3H, s); 3.19 (2H, d); 2.02 (3H, s); 1.70 (6H, q); 1.59 (6H, d).

b) 4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid, methyl ester

5% Rhodium on carbon (0.40 g) was added to a solution of (2E)-3-[4chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-2-propenoic acid, methyl ester (Example 6a, 2.2 g) in ethyl acetate/dichloromethane (4:1) (160 ml) and the mixture hydrogenated at 3 bar for 24 h The catalyst was removed by filtration and the filtrate concentrated to give the subtitled compound as an oil (2.3 g).

MS (APCI+ve) 390/392 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.55 (1H, d); 7.31 (1H, d); 7.20 (1H, dd); 6.26 (1H, t, br); 3.68 (3H, s); 3.17 (2H, d); 2.95 (2H, t); 2.63 (2H, t); 2.02 (3H, s); 1.70 (6H, q); 1.59 (6H, d).

c) 4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid

A solution of sodium hydroxide (0.475 g) in water (30 ml) was added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid, methyl ester (Example 6b, 2.3 g) in methanol (30 ml) After 5 h the reaction mixture was reduced to half volume in vacuo and acidified with dilute hydrochloric acid. A white solid precipitated and was collected by filtration and dried in vacuo at 50° C., to give the subtitled compound (1.2 g).

MS (APCI+ve) 376/378 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 11.18 (1H, s); 8.28 (1H, t); 7.37 (1H, d); 7.28 (1H, dd); 7.26 (1H, d); 2.92 (2H, d); 2.82 (2H, t); 2.54 (2H, t); 1.94 (3H, s); 1.63 (6H, q); 1.52 (6H, s).

d) 2-Chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Isobutylchloroformate (0.575 ml) and triethylamine (0.63 ml) were added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid (Example 6c, 1.64 g) in tetrahydrofuran (30 ml) at 0° C. After 1 h the precipitates were removed by filtration and the filtrate added portionwise to a solution of sodium borohydride (0.18 g) in water (10 ml) at 10° C. After a further 1 h the reaction mixture was poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was extracted twice with dilute hydrochloric acid, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography (eluting with dichloromethane/methanol 96:4); yielded the subtitled compound as a solid (1.3 g).

MS (APCI+ve) 362/364 (MH) ⁺

¹ H NMR (CDCl ₃ ) δ 7.55 (1H, d); 7.31 (1H, d); 7.19 (1H, dd); 6.28 (1H, s, br); 3.66 (2H, t); 3.17 (2H, d); 2.72 (2H, t); 1.92 (3H, s); 1.88 (2H, quin); 1.68 (6H, q); 1.59 (6H, s); 1.28 (1H, t).

e) 2-Chloro-5-[3-[(methylsulfonyl)oxylpropyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide

Methanesulfonyl chloride (1.1 ml) and triethylamine (2 ml) were added to a solution of 2-chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 6d, 2.65 g) in dichloromethane at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted once with water, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the subtitled compound as an oil which slowly solidified (3.2 g).

MS (APCI+ve) 440/442 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.55 (1H, d); 7.34 (1H, d); 720(1H, dd); 6.32 (1H, t, br); 4.21 (2H, t); 3.18 (2H, d); 3.01 (3H, s); 2.77 (2H, t); 2.09 (2H, quin); 2.01 (3H, s); 1.69 (6H, q); 1.59 (6H, d).

f) 2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3 .1.1 ^3,7 ]dec-1-ylmethyl)benzamide, acetate salt

Ethanolamine (0.07 ml) was added to a suspension of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 6e, 0.170 g) in n-butanol (5 ml) and heated at 100° C. in a sealed tube for 12 h. On cooling to ambient temperature the solution was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrite in 0.1% aqueous ammoiium acetate/25–95%) gave the title compound as the acetate salt (0.070 g).

MS (APCI+ve) 405/407 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.28 (1H, t); 7.36 (1H, d); 7.25 (1H, dd); 7.20 (1H, d); 3.44 (2H, t); 2.92 (2H, d); 2.50–2.65 (6H, m); 1.94 (3H, s); 1.87 (3H, s); 1.74–1.61 (8H, m); 1.52 (6H, s).

EXAMPLE 7

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricycl o[3.3.1.1 ^3,7 dec-1-ylmethyl)-benzamide, hydrochloride salt

3-Aminopropanol (1 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.270 g, Example 6e) in tetrahydrofuran (30 ml) and the solution heated at reflux for 12 h. On cooling to ambient temperature the reaction mixture was diluted with water and extracted thrice with dichloromethane. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC eluting with a gradient of acetonitrile/0.1% aqueous ammonium acetate (25–95%), gave the title compound as the acetate salt. Treatment with 4M hydrochloric acid in dioxane gave the title compound as the hydrochloride salt (0.070 g).

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.67 (2H, s); 8.31 (1H, t); 7.41(1H, d); 7.30–7.25 (2H, m); 4.74 (1H, t); 3.47 (2H, q); 2.95–2.85 (6H, m); 2.67 (2H, t); 2.00–1.84 (5H, m); 1.76 (2H, quin); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 8

2-Chloro-5-[3-(methylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetate salt

Methylamine (2M tetrahydrofuran, 8 ml) was added to 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) and heated in a sealed tube at 70° C. for 18 h. On cooling to ambient temperature, the solution was diluted with ethyl acetate and extracted twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) gave the title compound as the acetate salt (0.140 g).

MS (APCI+ve) 375/377 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.30 (1H, t); 7.37 (1H, d); 7.24 (1H, dd); 7.21 (1H, d); 2.92 (2H, d); 2.62 (2H, t); 2.53 (2H, t); 2.30 (3H, s); 1.94 (3H, s); 1.86 (3H, s); 1.57–1.77 (8H, m); 1.52 (6H, s).

EXAMPLE 9

2-Chloro-5-[3-[(1-methylethyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Isopropylamine (0.5 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in tetrahydrofuran (20 ml) and heated at 70° C. in a sealed tube for 24 h. The mixture was concentrated under reduced pressure and the residue purified by solid phase extraction on SCX resin. The title product was isolated as the hydrochloric acid salt (0.10 g).

MS (APCI+ve) 403/405 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.67 (2H, s); 8.31 (1H, t); 7.41 (1H, d); 7.30 (1H, dd); 7.26 (1H, d); 3.33–3.22 (1H, m); 2.93 (2H, d); 2.87 (2H, s); 2.69 (2H, t); 1.86–1.95 (5H, m); 1.63 (6H, q); 1.52 (6H, s); 1.22 (6H, d).

EXAMPLE 10

5-[3-[(2-Amino-2-methylpropyl)amino]propyl]-2-chloro-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt

2-Methyl-1,2-propanediamine (0.12 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) gave the title compound as the acetate salt. Treatment with 4M hydrochloric acid in dioxane gave the title compound as the dihydrochloride salt (0.045 g).

MS (APCI+ve) 432/434 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 9.40 (2H, m); 8.60 (3H, m); 8.32 (1H, t); 7.41 (1H, d); 7.31 (1H, d); 7.27 (1H, s); 3.20 (2H, s); 2.92 (4H, d); 2.71 (2H, t); 2.01 (2H, quin); 1.94 (3H, s); 1.63 (6H, q); 1.52 (6H, s); 1.39 (6H, s).

EXAMPLE 11

2-Chloro-5-[3-[(4-hydroxybutyl)amino]propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

4-Amino-1-butanol (0.11 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.25 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesian sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) gave the title compound as the acetate salt. Treatment with aqueous 2M sodium hydroxide and extraction into ethyl acetate gave the title compound (0.065 g).

MS (APCI+ve) 433/435 M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.28 (1H, t); 7.35 (1H, d); 7.24 (1H, dd); 7.20 (1H, d); 3.37 (2H, t); 2.92 (2H, d); 2.63 (2H, t); 2.40–2.60 (4H, m); 1.92 (3H, s); 1.70–1.55 (8H, m); 1.52 (6H, s); 1.40–1.45 (4H, m).

EXAMPLE 12

2-Chloro-5-[3-[(2-hydroxy-2-methylpropyl)amino]propyl]-N -(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetate salt

2-Hydroxy-2-methyl-1-propylamine [prepared according to Journal American Chemical Society (1941), 63, p1034] (0.25 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in butan-1-ol (8 ml) and healed at 100° C. in a sealed tube for 24 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by solid phase extraction on SCX resin and preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25–95%) to give the title compound as the acetate salt (0.160 g).

MS (APCI+ve) 433/435 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.29 (1H, t); 7.36 (1H, d); 7.26 (1H, d); 7.21 (1H, s); 2.92 (2H, d); 2.63 (2H, t); 2.55 (2H, t); 2.40 (2H, s); 1.94 (3H, s); 1.88 (3H, s); 1.80–1.58 (8H, m); 1.52 (6H, s); 1.08 (6H, s).

EXAMPLE 13

2-Chloro-5-[3-[[2-(methylamino)ethyl]amino]propyl]-N-(tr icyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt

a) 2-Chloro-5-(3-oxopropyl)-benzoic acid

2-Chloro-5-iodobenzoic acid (5.0 g), tetrabutylammonium chloride (5.0 g), sodium hydrogencarbonate (5.3 g) and allyl alcohol (1.6 ml) were combined in N,N-dimethylformamide (50 ml) and PdCl ₂ (0.6 g) was added under nitrogen. After 24 h ethyl acetate and 2M hydrochloric acid were added to the crude reaction mixture and the precipitated Pd filtered off. The organic phase was separated and washed thrice with 2M hydrochloric acid then once with brine and dried over magnesium sulfate, filtered and evaporate. Purification by chromatography on silica (eluting ethyl acetate:acetic acid/19:1) gave the subtitled product as an oil (2.77 g).

MS m/z 212/214

¹ H NMR (CDCl ₃ ) δ 9.82 (1H, s); 7.83 (1H, d); 7.42 (1H, d); 7.30 (1H, dd); 2.98 (2H, t); 2.83 (2H, t).

b) 2-Chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl][2-[[(1,1-dimet hylethoxy)carbonyl]methylamino]ethyl]amino]propyl]-benzoic acid

Sodium triacetoxyborohydride (310 mg) was added to a solution of (2-aminoethyl)methyl-1,1-dimethylethyl carbamic acid ester [prepared according to J. Med. Chem (1990), 33(1), 100] (0.156 g) and 2-chloro-5-(3-oxopropyl)-benzoic acid (0.21 g, Example 13a) in methanol (15 ml). After 24 h, acetic acid (0.2 ml) was added and the mixture evaporated to dryness. The residue was redissolved in dichloromethane (10 ml), triethylamine. (0.45 ml) and (1,1-dimethylethoxy)carbonyl 1,1-dimethylethyl carbonic acid ester (1 g) was added. After 24 h the reaction mixture was washed twice with 10% KHSO ₄ , once with brine and dried over magnesium sulfate, filtered and evaporated. Purification by chromatography on silica (eluting with iso-hexane:ethyl acetate:acetic acid/80:20:1 then ethyl acetate:acetic acid/100:1) gave the subtitled product as an oil (0.2 g).

MS (APCI+ve) 471/473 (M+H) ⁺

c) 2-Chloro-5-[3-[[2-(methylamino)ethyl]amino]propyl]-N-(tricyc lo[(3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt

PyBrOP (0.2 g) was added to a solution of 2-chloro-5-[(3-[[(1,1-dimethylethoxy)carbonyl][2-[[(1,1-dime thylethoxy)carbonyl]methylamino]ethyl]-amino]propyl]-benzoic acid (0.2 g, Example 13b), adamantanemethylamine (0.1 ml) and triethylamine (0.15 ml) in N,N-dimethylformamide (10 ml). After 1 h the reaction mixture was diluted with ethyl acetate and washed with water, then washed twice with ammonium chloride solution, twice with saturated sodium hydrogencarbonate solution and once with brine. The organic extracts were dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica (eluting with dichloromethane:methanol/2–10%). The product was redissolved in dichloromethane:methanol/1:1 (15 ml) and 4M hydrochloric acid in dioxane (2 ml) added. The mixture was stirred until deprotection was complete then purified by prep RP-HPLC (acetonitrile/0.1% aqueous trifluoroacetic acid). Conversion to the hydrochloride salt by treatment with 4M hydrochloric acid in 1,4-dioxane/methanol gave the title compound (0.055 g).

MS (APCI+ve) 418/420 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 9.50–9.00 (4H, m); 7.42 (1H, d); 7.29 (1H, d); 7.27 (1H, s); 3.25 (4H, s, br); 3.05–2.90 (4H, m); 2.70 (2H, t); 2.60 (3H, s); 2.00–1.90 (5H, m); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 14

(S)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

a) 2-Chloro-5-iodo-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

2-Chloro-5-iodobenzoic acid (10.0 g) was suspended in dichloromethane (160 ml) then oxalyl chloride (4.0 ml) was added followed by N,N-dimethylformamide (40 μl). After 24 h the solvent was evaporated to afford a white solid, which was redissolved in dichloromethane (160 ml). Triethylamine (14.8 ml) was added followed by adamantylmethylamine (6.9 ml) with cooling to maintain a temperature below 30° C. The resulting cloudy mixture was stirred for 1 h, then evaporated to give a pale yellow solid. This was stirred in a mixture of ethyl acetate (400 ml) and 2M hydrochloric acid (300 ml) until the solid dissolved to give 2 clear phases. The (upper) organic phase was separated and washed with 2M aqueous sodium hydroxide solution (300 ml), then dried (Na ₂ SO ₄ ) and evaporated to a yellow solid. The solid was suspended in iso-hexane (100 ml), then filtered and washed with more iso-hexane (40 ml). The resulting off-white solid was dried in a vacuum oven at 40° C. (14.0 g).

MS (APCI+ve) 430/432 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 8.00 (1H, d); 7.66 (1H, dd); 7.14 (1H, d); 6.17 (1H, s, br); 3.17 (2H, d); 2.01 (3H, s); 1.69 (6H, q); 1.58 (6H, d).

b) 2-Chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

2-Chloro-5-iodo-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (5.00 g, Example 14a), tetrabutylammonium chloride (3.40 g) and sodium hydrogencarbonate (2.44 g) were charged to a flask. Pd(OAc) ₂ (0.0533 g), toluene (50 ml) and allyl alcohol (1.01 ml) were added to afford a pale brown mixture which was heated at 80° C. for 5 h. The resulting dark brown mixture was cooled to ambient then filtered to remove the solid residues. These were washed with further toluene (2×50 ml) and the combined toluene extracts then washed with water (100 ml), dried over MgSO ₄ and concentrated to a light brown solid (3.82 g).

MS (APCI+ve) 360/362 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 9.81 (1H, s), 7.56 (1H, s); 7.32 (1H, d); 7.19 (1H, d); 6.28 (1H, s, br); 3.18 (2H, d); 2.96 (2H, t); 2.81 (2H, t); 2.01 (3H, s); 1.70 (6H, q); 1.58 (6H, s).

c) (S)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tricycl o[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Sodium triacetoxyborohydride (0.6 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.5 g, Example 14b) and (S)-2-hydroxypropylamine (0.31 g) in dichloromethane (5 ml). After 24 h the crude reaction mixture was purified by flash chromatography (eluting with 5–20% methanol in dichloromethane+1% ammonia) and the hydrochloride salt precipitated from ether/methanol 19:1, to afford the title compound as a white solid (0.19 g).

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.70–8.40 (2H, d, br); 8.30 (1H, t); 7.41 (1H, d); 7.28 (1H, dd); 7.24 (1H, d); 5.32 (1H, d); 3.97–3.90 (1H, m); 3.00–2.85 (5H, m); 2.75 (1H, t); 2.65 (2H, t); 2.00–1.90 (5H, m); 1.64 (6H, q); 1.52 (6H, s); 1.09 (3H, d).

EXAMPLE 15

(R)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.70–8.40 (2H, d, br); 8.30 (1H, t); 7.41 (1H, d); 7.28 (1H, dd); 7.24 (1H, d); 5.32 (1H, d); 3.97–3.90 (1H, m); 3.00–2.85 (5H, m); 2.75 (1H, t); 2.65 (2H, t); 2.00–1.90 (5H, m); 1.64 (6H, q); 1.52 (6H, s); 1.09 (3H, d).

EXAMPLE 16

(R)-2-Chloro-5-[3-[(2-hydroxy-1-methylethyl)amino]propyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.80–8.40 (2H, d, br); 8.31 (1H, t); 7.42 (1H, d); 7.28 (1H, dd); 7.25 (1H, d); 5.36 (1H, s); 3.65–3.60 (1H, d, br); 3.55–3.45 (1H, m); 3.25–3.15 (1H, m); 2.95–2.85 (4H, m); 2.65 (2H, t); 2.00–1.90 (5H, m); 1.63 (6H, q); 1.52 (6H, s); 1.20 9 3H, d).

EXAMPLE 17

2-Chloro-5-[3-[[2-hydroxy-1-(hydroxymethyl)-1-methylethy l]amino]propyl]-N-(tricyclo[3,3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the method described for Example 14.

MS (APCI+ve) 449/451 (M+H) ⁺

¹ H NMR DMSO-d ₆ ) δ 8.27 (1H, t); 7.36 (1H, d); 7.24 (1H, dd); 7.21 (1H, d); 4.32 (2H, s); 3.22 (4H, s); 2.92 (2H, d); 2.65 (2H, t); 2.45 (2H, q(on edge of DMSO)); 1.92 (3H, s); 1.70–1.57 (8H, m); 1.52 (6H, s); 0.85 (3H, s).

EXAMPLE 18

5-[3-[[2-(Acetylamino)ethyl]amino]propyl]-2-chloro-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

MS (APCI+ve) 446/448 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.90 (2H, s, br); 8.32 (1H, t); 8.22 (1H, t); 7.41 (1H, d); 7.28 (1H, dd); 7.24 (1H, d); 3.33 (2H, q); 2.95–2.85 (6H, m); 2.63 (2H, t); 2.00–1.86 (5H, m); 1.84 (3H, s); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 19

2-Chloro-5-[3-[[2-(diethylamino)ethyl]amino]propyl]-N-(t ricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt

Prepared according to die method described for Example 14.

MS (APCI+ve) 460/462 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 10.70 (1H, s); 9.48 (2H, s); 8.31 (1H, t); 7.42 (1H, d); 7.30 (1H, dd); 7.27 (1H, d); 3.50–3.30 (2H, m); 3.25–3.10 (4H, m); 3.00–2.90 (4H, d, br); 2.71 (2H, t); 2.00–1.90 (5H, m); 1.63 (6H, q); 1.52 (6H, s); 1.24 (6H, t).

EXAMPLE 20

2-Chloro-5-[3-[(3-methoxypropyl)amino]propyl]-N-(tricycl o[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

MS (APCI+ve) 433/435 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.77 (2H, s, br); 8.31 (1H, t); 7.41 (1H, d); 7.28 (1H, dd); 7.25 (1H, d); 3.40 (2H, t); 3.23 (3H, s); 3.00–2.75 (6H, m); 2.67 (2H, t); 2.00–1.80 (7H, m); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 21

2-Chloro-5-[3-[(3-hydroxy-3-methylbutyl)amino]propyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

MS (APCI+ve) (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.57 (2H, s, br); 8.30 (1H, t); 7.42 (1H, d); 7.29 (1H, dd); 7.25 (1H, d); 4.61 (1H, s); 3.05–2.85 (6H, m); 2.64 (2H, t); 2.00–1.82 (5H, m); 1.73–1.53 (8H, m); 1.52 (6H, s); 1.12 (6H, s).

EXAMPLE 22

2-Chloro-5-[3-[(2-methoxyethyl)amino]propyl]-N-(tricylo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Prepared according to the method described for Example 14.

mp 245–248° C.

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.79 (2H, s); 8.30 (1H, t); 7.41 (1H, d); 7.27 (1H, dd); 7.25 (1H, d); 3.58 (2H, t); 3.30 (3H, s); 3.09 (2H, s, br); 2.95–2.85 (4H, m); 2.67 (2H, t); 1.95–1.86 (5H, m); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 23

2-Chloro-5-[[3-(methylamino)propoxy]methyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl) benzamide

a) 2-Chloro-5-[[3-[[(1,1-dimethylethoxy)carbonyl]methylamino]pr opoxy]methyl]-benzoic acid

(3-Hydroxypropyl)methyl-carbamic acid, 1,1-dimethylethyl ester (0.272 g) in tetrahydrofuran (5 ml) was cooled to 0° C. under nitrogen. Sodium hydride (60% dispersion in oil, 0.110 g) was added. The mixture was allowed to warm to room temperature and is stirred for 30 min. 5-(Bromomethyl)-2-chloro-benzoic acid (0.300 g) in tetrahydrofuran (3 ml) was added and the mixture heated at 55° C. for 6 h. The solution was cooled, poured into saturated aqueous potassium hydrogensulfate solution, extracted into ethyl acetate (×3), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound (0.431 g).

MS (ESI+ve) 358 (M+H) (ESI−ve) 356 (M−H) ⁺

b) [3-[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]propyl] methyl-carbamic acid, 1,1-dimethylethyl ester

2-Chloro-5-[[3-[[(1,1-dimethylethoxy)carbonyl]methylamino ]propoxy]methyl]-benzoic acid (0.318 g, Example 23a), carbonyl diimidazole (0.165 g) and dimethylformamide (10 ml) were heated at 50° C. under nitrogen for 30 min. The mixture was allowed to cool to room temperature and 1-adamantanemethylamine (0.18 ml) was added. The mixture was stirred at room temperature for 20 h then poured into ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution followed by brine. The solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluting with 2:1 isohexane/ethyl acetate) to afford the subtitled compound (0.236 g).

MS (ESI+ve) 505 (M+H) ⁺

c) 2-Chloro-5-[[3-(methylamino)propoxy]methyl]-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

[3-[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]propyl] methyl-carbamic acid, 1,1-dimethylethyl ester (0.236 g, Example 23b), 4M hydrogen chloride in 1,4-dioxane (5 ml) and methanol (5 ml) were stirred together under nitrogen for 3 h, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica gel, eluting with 19:1:0.1/dichloromethane:methanol:ammonia to afford the title compound as an oil (0.106 g).

MS (APCI+ve) 405/407 (MH) ⁺

¹ H NMR (CDCl ₃ ) δ 7.64 (1H, s); 7.39–7.33 (2H, m); 6.29 (1H, t br); 4.49 (2H, s); 3.55 (2H, t); 3.18–3.17 (2H, d); 2.72–2.68 (2H, t); 2.44 (3H, s); 2.01 (3H, s, br); 1.86–1.79 (2H, m); 1.75–1.63 (6H, m); 1.59 (6H, s).

EXAMPLE 24

2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt

a) 5-(Bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

To a solution of 2-chloro-5-(bromomethyl)-benzoic acid (1.0 g) in dichloromethane (25 ml) at 0° C. was added dimethylformamide (0.05 ml) followed by oxalyl chloride (0.52 ml). The reaction was allowed to warm to room temperature and stirred for 30 min. The volatiles were removed under vacuum and the residue dried under high vacuum. The residue was dissolved in dichloromethane (20 ml) and added to a solution of 2-adamantanemethylamine hydrochloride salt (0.95 g) in dichloromethane (20 ml) and diisopropylethylamine (2 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. The organics were washed with water (20 ml) then saturated aqueous ammonium chloride solution and the organic layer dried over magnesium sulfate then filtered. The filtrate was concentrated under reduced pressure to a solid. The crude material was recrystallised from dichloromethane/hexane to afford the subtitled compound as a white solid (1.3 g).

b) [2-[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]ethyl]( 2-hydroxyethyl)-carbamic acid, 1,1-dimethylethyl ester

A mixture of 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 24a, 0.300 g), bis(2-hydroxyethyl)-carbamic acid, 1,1-dimethylethyl ester (0.312 g) and silver trifluoroacetate (0.336 g) in dichloromethane (30 ml) was stirred under nitrogen at room temperature for 20 h. The solution was then decanted from the silver salts and the dichloromethane removed under vacuum. The crude material was purified on silica gel (eluting with ethyl acetate) to afford the subtitled compound as an oil (0.249 g).

MS (ESI+ve) MW 521/523 (M+H)+

c) 2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N(tricy clo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt

[2-[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]ethyl]( 2-hydroxyethyl)-carbamic acid, 1,1-dimethylethyl ester (0.286 g, Example 23b), 4M hydrogen chloride in 1,4-dioxane (10 ml) and methanol (10 ml) were stirred together under nitrogen for 20 h, poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica gel, eluting with 19:1:0.1/dichloromethane:methanol:ammonia and further purified by reverse-phase hplc (75:25 to 5:95/0.1% aqueous ammonium acetate:acetonitrile) to afford the title compound as an oil (0.051 g).

MS (APCI+ve) 421/423 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.66 (1H, d); 7.38 (1H, d); 7.31 (1H dd); 6.68 (1H, t, br); 4.52 (2H, s); 3.72 (2H, t); 3.63 (2H, t); 3.17 (2H, d); 2.95 (2H, t); 2.85 (2H, t); 2.01 (3H, s, br); 1.91 (2H, s); 1.75–1.63 (6H, m); 1.59 (6H, s).

EXAMPLE 25

2-Chloro-5-[[2-[(3-hydroxypropyl)amino]ethoxy]methyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt

a) 2-Chloro-5-[(2-hydroxyethoxy)methyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

A mixture of 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 24a, 0.300 g), ethylene glycol (0.094 g) and silver trifluoroacetate (0.336 g) in dichloromethane (10 ml) was stirred under nitrogen at room temperature for 20 h. The solution was then decanted from the silver salts and the dichloromethane removed under vacuum. The crude material was purified on silica (eluting with ethyl acetate) to afford the subtitled compound as an oil (0.228 g).

MS (ESI+ve) MW 378/380 (M+H) ⁺

b) 2-Chloro-5-[[2-[(methylsulfonyl)oxy]ethoxy]methyl]-N-(tricyc lo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

2-Chloro-5-[(2-hydroxyethoxy)methyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.228 g, Example 25a) and triethylamine (0.21 ml) in dichloromethane (10 ml) were cooled to 5° C. under nitrogen and methanesulfonyl chloride (0.1 ml) was added. The mixture was stirred at room temperature for 20 h then poured into 2N hydrochloric acid, and extracted into ethyl acetate. The combined extracts were washed with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution then brine, and dried over magnesium sulfate. The organics were filtered and concentrated under reduced pressure to afford the subtitled compound as a white solid (0.160 g).

¹ H NMR (CDCl ₃ ) δ 7.66 (1H, s); 7.41–7.33 (2H, m); 6.32 (1H, t, br); 4.57 (2H, s); 4.40–4.38 (2H, m); 3.77–3.75 (2H, m); 3.17–3.15 (2H, d); 3.04 (3H, s); 2.01 (3H, s, br); 1.75–1.64 (6H, m); 1.59 (6H, s, br).

c) 2-Chloro-5-[[2-[(3-hydroxypropyl)amino]ethoxy]methyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt

2-Chloro-5-[[2-[(methylsulfonyl)oxy]ethoxy]methyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.160 g, Example 25b), 3-amino-1-propanol (0.27 ml) and n-butanol (4 ml) were heated together in a sealed tube at 110° C. for 24 h. The mixture was cooled, poured into 2N sodium hydroxide solution and extracted into ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography over silica gel (eluting with 19:1:0.1/dichloromethane methanol:ammonia) and further purification by reverse-phase HPLC (75:25 to 5:95/0.1% aqueous ammonium acetate:acetonitrile) afforded the title compound as a white solid (0.081 g).

MS (APCI+ve) 435/437 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.75 (1H, s); 7.37 (1H, d); 7.27 (1H d); 6.83 (1H, t, br); 4.56 (2H, s); 3.90 (4H, s, br); 3.21 (4H, s, br); 3.17 (2H, d); 2.01 (5H, s, br); 1.75–1.63 (6H, m); 1.59

EXAMPLE 26

2-Chloro-5-[[[3-[(1-methylethyl)amino]propyl]amino]methy l]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

a) 5-Bromo-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

To a suspension of 5-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and DMF (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was diluted with dichloromethane and washed in sequence with water, 10% aqueous potassium carbonate solution, 10% aqueous potassium hydrogen sulfate and saturated brine. The organiuc phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound as a solid (7.84 g).

MS (APCI+ve) 383/385 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.42 (1H, t); 7.63 (1H, dd); 7.57 (1H, m); 7.45 (1H, d), 2.93 (2H, d); 1.94 (3H, s, br); 1.69–1.58 (6H, m); 1.51 (6H, s).

b) 2-Chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (3.25 g, Example 25a) in tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of 1.4M methyllithium in diethyl ether (6.1 ml) was added to this solution over 2 min. The mixture was stirred at −78° C. for 10 min, then a 1.7M solution of tert-butyllithium in pentane (10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min, then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min, quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitled compound as a solid (/2.76 g).

MS (APCI+ve) 332/334 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 10.04 (1H, s); 8.49 (1H, t); 7.96–7.91 (2H, m); 7.74 (1H, d); 2.96 (2H, d), 1.95 (3H, s); 1.64 (6H, m); 1.53 (6H, d).

c) 2-Chloro-5-[[[3-[(1-methylethyl)amino]propyl]amino]methyl]-N -(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

A mixture of 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.244 g, Example 25b), N-isopropyl-1,3-propanediamine (0.211 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 h. The mixture was cooled and concentrated under reduced pressure to an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.040 g) was added portionwise and the mixture stirred at room temperature for 30 min, then concentrated under reduced pressure and the residue purified by column chromatography over silica (eluting with 9:1:0.1 dichloromethane/methanol/35% aqueous ammonia) to give the title compound (0.015 g) and a by-product (see Example 27).

MS (APCI+ve) 432/434 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.64 (1H, s); 7.37–7.32 (2H, m); 6.28 (1H s, br); 3.78 (2H, s); 3.18 (2H, d); 2.84–2.74 (1H, m); 2.70–2.64 (4H, m); 2.01 (3H, s, br); 1.76–1.63 (8H, m); 1.59 (6H, s, br); 1.05 (6H, d).

EXAMPLE 27

5-[[(3-Aminopropyl)amino]methyl]-2-chloro-N-(tricyclo[3. 3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Formed as a by-product in Example 26c above (0.125 g).

MS (APCI+ve) 390/392 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.65 (1H, s); 7.37–7.32 (2H, m); 6.31 (1H, t, br); 3.79 (2H, s); 3.18 (2H, d); 2.77 (2H, t); 2.68 (2H, t); 2.01 (3H, s, br); 1.75–1.61 (8H, m); 1.59 (6H, s, br).

EXAMPLE 28

2-Chloro-5-[[[2-[(1-methylethyl)amino]ethyl]amino]methyl ]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Synthesized as in Example 26 using 2-chloro-5-formyl-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.500 g, Example 25b) and N-isopropylethylenediamine (0.186 g) to give the title compound as a solid (0.105 g).

MS (APCI+ve) 418/420 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.65 (1H, s); 7.34 (2H, s); 6.26 (1H, t, br); 3.79 (2H, s); 3.18 (2H, d); 2.79–2.69 (5H, m); 2.01 (3H, s, br); 1.75–1.64 (6H, m); 1.59 (6H, s, br); 1.50 (2H, s, br), 1.05 (6H, d).

EXAMPLE 29

3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-propyl]amino]pr opanoic acid, 2,2-dimethylpropyl ester, trifluoroacetic acid salt

a) 2-Chloro-5-iodo-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

2-Chloro-5-iodobenzoic acid (10.0 g) was suspended in dichloromethane (160 ml) then oxalyl chloride (4.0 ml) was added followed by N,N-dimethylformamide (40 μl). After 24 h the solvent was evaporated to afford a white solid, which was then redissolved in dichloromethane (160 ml). Triethylamine (14.8 ml) was added, followed by adamantane methylamine (6.9 ml) with cooling to keep the temperature below 30° C. The resulting slightly cloudy mixture was stirred for 1 h, then solvent was evaporated to give a pale yellow solid. The solid was stirred in a mixture of ethyl acetate (400 ml) and 2M hydrochloric acid (300 ml) until the solid dissolved to afford two clear phases. The (upper) organic phase was separated off and washed with 2M sodium hydroxide solution (300 ml), then dried (Na ₂ SO ₄ ) and evaporated to a yellow solid. The solid was suspended in iso-hexane (10 ml), then filtered and washed with more iso-hexane (40 ml), and the resulting off-white solid dried in vacuo at 40° C. to afford the subtitled compound (14.0 g).

MS (APCI+ve) 430/432 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 8.00 (1H, d); 7.66 (1H, dd); 7.14 (1H, d); 6.17 (1H, s, br); 3.17 (2H, d); 2.01 (3H, s); 1.69 (6H, q); 1.58 (6H, d).

b) 2-Chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

2-Chloro-5-iodo-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (5.00 g Example 29a), tetrabutylammonium chloride (3.40 g) and sodium hydrogencarbonate (2.44 g) were charged to a flask, followed by Pd(OAc) ₂ (53.3 mg), toluene (50 ml) and allyl alcohol (1.01 ml). The pale brown mixture was heated at 80° C. for 5 h, then cooled to ambient temperature. The mixture was filtered and the residues washed with additional toluene (50 ml+50 ml). The combined toluene solutions were washed with water (100 ml), then dried over MgSO ₄ and evaporated to a light brown solid (3.82 g).

MS (APCI+ve) 360/362 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 9.81 (1H, s), 7.56 (1H, s); 7.32 (1H, d); 7.19 (1H, d); 6.28 (1H, s, br); 3.18 (2H, d); 2.96 (2H, t); 2.81 (2H, t); 2.01 (3H, s); 1.70 (6H, q); 1.58 (6H, s).

c) 2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3. 3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Sodium triacetoxyborohydride (1.86 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (1.57 g, Example 29b) and 3-amino-1-propanol(0.8 ml) in dichloromethane (150 ml). After 24 h the crude reaction mixture was purified by chromatography (eluting with 5–20% methanol in dichloromethane+1% ammonia) to give the subtitled compound as a white solid (1.05 g).

MS (APCI+ve) 419/421 (M+H) ⁺

d) 3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-phenyl]propyl][(1,1-di ethylethoxy)carbonyl]amino]propanoic acid, 2,2-dimethylpropyl ester

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.271 g, Example 29c), N,N-diisopropylethylamine (0.50 ml) and tetrahydrofuran (10 ml) were stirred together under nitrogen. Trimethylacetyl chloride (0.26 ml) was added dropwise and the mixture stirred at room temperature for 48 h, then poured into water and extracted into ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure and chromatographed over silica (eluting with 4:1 isohexanelethyl acetate) to give the subtitled compound (0.158 g) as an oil.

MS (ESI+ve) 603/605 (M+H) ⁺

e) 3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]-phenyl]propyl]amino]pr opanoic acid, 2,2-dimethylpropyl ester, trifluoroacetic acid salt

3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 dec-1-ylmethyl)amino]carbonyl]-phenyl]propyl][(1,1-dim ethylethoxy)carbonyl]amino]propanoic acid, 2,2-dimethylpropyl ester (0.158 g, Example 29d), trifluoroacetic acid (2 ml) and dichloromethane (2 ml) were stirred together under nitrogen for 15 min, then concentrated under reduced pressure to give the title compound (0.170 g).

MS (APCI+ve) 503/505 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.40 (1H, d); 7.32 (1H, d), 7.14 (1H dd); 4.12 (2H, t); 3.16 (2H, d); 3.09–2.89 (4H, m); 2.64 (2H, t); 2.06–1.92 (7H, m); 1.75–1.63 (6H, m); 1.58 (6H, s); 1.18 (9H, s).

EXAMPLE 30

5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

a) 2-Chloro-5-(cyanomethyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

Potassium cyanide (525 mg) and 18-crown-6 (150 mg) were added to a solution of 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 24a, 1.8 g) in ethanol (50 ml) and the mixture heated under reflux for 24 h. On cooling the reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The organics were separated, washed with brine, dried over magnesium sulfate, filtered and evaporated. Purification by chromatography on silica (eluting with a gradient of iso-hexane/ethyl acetate/4:1 to 6:4) gave the subtitled product as a pink solid (1.0 g).

MS (APCI+ve) 343/345 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.38 (1H, t); 7.52 (1H, d); 7.43–7.38 (2H, m); 4.08 (2H, s); 2.94 (2H, d); 1.92 (3H, s); 1.63 (6H, q); 1.52 (6H, s).

b) [2-[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-ethyl]carbamic acid, 1,1-dimethylethyl ester

Sodium borohydride (1.6 g) was added portionwise to a cooled solution of 2-chloro-5-(cyanomethyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide (Example 30a, 2.1 g), (1,1-dimethylethoxy)carbonyl carbonic acid, 1,1-dimethylethyl ester (2.67 g) and cobalt(II)chloride (1.6 g) in methanol (100 ml). After 1.5 h the solvent was evaporated and the residue slurried between ethyl acetate and saturated sodium hydrogencarbonate solution and the insoluble cobalt salts filtered. The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and evaporated to give the subtitled product as a foam (2.2 g).

MS (APCI+ve) 447/449 (M+H) ⁺

¹ H NMR (CDCl ₃ ) δ 7.54 (1H, d); 7.34 (1H, d); 7.19 (1H, dd); 6.28 (1H, s, br), 4.54 (1H, s, br); 3.39 (2H, q); 3.18 (2H, d); 2.80 (2H, t); 2.04 (3H, s); 1.70 (6H, q); 1.64 (6H, s); 1.42 (9H, s).

c) 5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, hydrochloride salt

Hydrochloric acid (4M in 1,4-dioxane, 3.0 ml) was added to a solution of [2-[4-chloro-3-[[(tricyclo(3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]ethyl]carbamic acid, 1,1-dimethylethyl ester (2.2 g, Example 30b) in methanol/dichloromethane (1:1) (50 ml). After 24 h the solvent was evaporated to leave the title compound as a foam (1.85 g).

MS (APCI+ve) 347/349 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.31 (1H, t); 8.15 (3H, s, br); 7.43 (1H, d); 7.31 (2H, m); 3.05–2.98 (2H, m); 2.95–2.85 (4H, m); 1.94 (3H, s); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 31

2-Chloro-5-[3-[(2-hydroxyethyl)pentylamino]propyl]-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl) benzamide

Prepared according to the procedure described in Example 6f

MS (APCI+ve) 475/477 (M+H) ⁺

EXAMPLE 32

2-Chloro-5-[3-(methyl-2-propeenylamino)propyl]-N-(tricyc lo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 415/417 (M+H) ⁺

EXAMPLE 33

2-Chloro-5-[3-[[2-(dimethylamino)ethyl]methylamino]propy l]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 446/448 (M+H) ⁺

EXAMPLE 34

5-[3(Butylethylamino)propyl]-2-chloro-N-(tricyclo[3.3.1. 1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 445/447 (M+H) ⁺

EXAMPLE 35

2-Chloro-5-[3-(methylpentylamino)propyl]-N-(tricyclo[3.3 .1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in 6f

MS (APCI+ve) 445/447 (M+H) ⁺

EXAMPLE 36

2-Chloro-5-[3-[[2-(diethylamino)ethyl]ethylamino]propyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 498/490 (M+H) ⁺

EXAMPLE 37

2-Chloro-5-[3-[(2-hydroxyethyl)methylamino]propyl]-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 419/421 (M+H) ⁺

EXAMPLE 38

2-Chloro-5-[3-(dipropylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 445/447 (M+H) ⁺

EXAMPLE 39

2-Chloro-5-[3-[(2-hydroxyethyl)(1-methylethyl)amino]prop yl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 447/449 (M+H) ⁺

EXAMPLE 40

5-[3-[Butyl(2-hydroxyethyl)amino]propyl]-2-chloro-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 461/463 (M+H) ⁺

EXAMPLE 41

2-Chloro-5-[3-(diethylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 417/419 (M+H) ⁺

EXAMPLE 42

2-Chloro-5-[3-(dimethylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 389/391 (M+H) ⁺

EXAMPLE 43

5-[3-(Butylmethylamino)propyl]-2-chloro-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 431/433 (M+H) ⁺

EXAMPLE 44

2-Chloro-5-[3-[(2-hydroxyethyl)propylamino]propyl[-N-(tr icyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 447/449 (M+H) ⁺

EXAMPLE 45

2-Chloro-5-[3-[ethyl(2-hydroxyethyl)amino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 433/435 (M+H) ⁺

EXAMPLE 46

2-Chloro-5-[3-(dibutylamino)propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

EXAMPLE 47

2-Chloro-5-[3-(ethylpropylamino)propyl]-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 431/433 (M+H) ⁺

EXAMPLE 48

2-Chloro-5-[3-[methyl(1-methylethyl)amino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 417/419 (M+H) ⁺

EXAMPLE 49

2-Chloro-5-[3-[[3-(dimethylamino)propyl]methylamino]prop yl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 460/462 (M+H) ⁺

EXAMPLE 50

2-Chloro-5-[3-[cyclohexyl(2-hydroxyethyl)amino]propyl]-N -(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 487/489 (M+H) ⁺

EXAMPLE 51

2-Chloro-5-[3-(cyclohexylmethylamino)propyl]-N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 457/459 (M+H) ⁺

EXAMPLE 52

2-Chloro-5-[3-(cyclohexylamino)propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 443/445 (M+H) ⁺

EXAMPLE 53

2-Chloro-5-[3-[[1-(hydroxymethyl)-2,2-dimethylpropyl]ami no]propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 461/463 (M+H) ³⁰

EXAMPLE 54

2-Chloro-5-[3-(cyclopropylamino)propyl]-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 401/403 (M+H) ⁺

EXAMPLE 55

2-Chloro-5-[3-[[2-(dimethylamino)ethyl]amino]propyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 432/434 (M+H) ⁺

EXAMPLE 56

2-Chloro-5-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propy l]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 447/449 (M+H) ⁺

EXAMPLE 57

2Chloro-5-[3-[(1,1-dimethylethyl)amino]propyl]-N-(tricyc lo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 417/419 (M+H) ⁺

EXAMPLE 58

2Chloro-5-[3-[[3-(dimethylamino)propyl]amino]propyl]-N-( tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 446/448 (M+H) ⁺

EXAMPLE 59

2-Chloro-5-[3-(cyclopentylamino)propyl]-N-(tricyclo[3.3. 1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 429/431 (M+H) ⁺

EXAMPLE 60

2-Chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-5-[3-[(1,2,2-trimethylpropyl)amino]pr opyl]-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 445/4476 (M+H) ⁺

EXAMPLE 61

5-[[3-(Butylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 417/419 (M+H) ⁺

EXAMPLE 62

2-Chloro-5-[3-[[1-(hydroxymethyl)-2-methylpropyl]amino]p ropyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 447/449 (M+H) ⁺

EXAMPLE 63

2Chloro-5-[3-[(1-methylpropyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 417/419 (M+H) ⁺

EXAMPLE 64

2-Chloro-5-[3-[[2-(methylthio)ethyl]amino]propyl]-N-(tri cyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 435/437 (M+H) ⁺

EXAMPLE 65

2-Chloro-5-[3-[(2-hydroxy-1,1-dimethylethyl)amino]propyl ]-N-(tricyclo(3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 433/435 (M+H) ⁺

EXAMPLE 66

2-Chloro-5-[3-[(cyclohexylmethyl)amino]propyl]-N-(tricyc lo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 457/459 (M+H) ⁺

EXAMPLE 67

2-Chloro-5-[3-(2-propenylamino)propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 401/403 (M+H) ⁺

EXAMPLE 68

2-Chloro-5-[3-[(2-fluoroethyl)amino]propyl]-N-(tricyclo[ 3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 407/409 (M+H) ⁺

EXAMPLE 69

2-Chloro-5-[3-[(2-methoxy-1-methylethyl)amino]propyl]-N- (tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

Prepared according to the procedure described in Example 6f.

MS (APCI+ve) 433/435 (M+H) ⁺

EXAMPLE 70

2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricycl o[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, dihydrochloride salt

a) 2-Chloro-5-(3-iodopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl) benzamide

2-Chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (5.9 g, Example 6d), iodine (6.2 g, 24.4 mmol), triphenylphosphine (6.4 g, 24.4 mmol) and imidazole (1.66 g, 24.4 mmol) were stirred in dichloromethane (100 ml) at room temperature for 1 h. The reaction was quenched with sat. aq. Na ₂ S ₂ O ₃ and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO ₄ ), concentrated and purified by column chromatography on silica (eluting with EtOAc:isohexane/1:3) to afford the subtitled compound as a pale yellow solid (6.8 g)

MS (APCI+ve) 472/474 (M+H) ⁺ .

b) 2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3. 3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide, dihydrochloride salt

Silver trifluoroacetate (0.7 g, 3.2 mmol) was added to 1,1-dimethylethyl (3-hydroxypropyl)methyl carbamic acid (1.8 g, 9.5 mmol), [Synth. Commun. (1995), 25(14), 2135–43] in dichloromethane (20 ml). After 10 min. 2-chloro-5-(3-iodopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl) benzamide (1.0 g, Example 70a) was added and the mixture was stirred for 24 h The resulting mixture was washed with water and concentrated. Treatment with 4M hydrochloric acid in 1,4-dioxane/methanol, concentration and purification by RPHPLC gave the title compound (26 mg) as a white solid.

MS (APCI+ve) 433/435 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) 8.79–8.35 (1H, m), 8.29 (1H, t, J=6.2 Hz), 7.38 (1H, d, J=8.1 Hz), 7.31–7.14 (m, 2H), 3.48–3.31 (4H, m), 2.98–2.81 (4H, m), 2.63 (2H, t, J=7.6 Hz), 2.50 (3H, s), 1.94 (3H, s), 1.87–1.73 (4H, m), 1.64 (6H, m), 1.52 (6H, m)

EXAMPLE 71

5-[[[(1-Aminocyclopropyl)methyl](2-hydroxyethyl)amino]me thyl]-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide.

a) 5-Bromomethyl-2-chloro-benzoic acid

To a stirred solution of 2-chloro-5-methyl-benzoic acid (25 g) in chloroform (500 ml) at 50° C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueous hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitled compound (17 g).

b) 5-Bromomethyl-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

To a stirred solution of 5-bromomethyl-2-chloro-benzoic acid (Example 71 a, 12.4 g) in dichloromethane (250 ml) and dimethylformamide (0.12 ml) at 0° C. was added oxalyl chloride (8.7 ml). The cooling bath was removed and the solution allowed to warm to room temperature. Once gas evolution had ceased the solution was concentrated in vacuo. The residue was redissolved in dichloromethane (300 ml), cooled to 0° C. and treated with diisopropylethylamine (12.4 ml) and adamantylmethylamine (7.54 ml). After 15 min at 0° C. the solution was poured into diethyl ether (1 L) and washed with 1N aqueous hydrochloric acid followed by brine. The organics were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a white powder (19 g)

MS (APCI+ve) 396/398 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.39 (1H, t); 7.50–7.40 (2H, m); 4.74 (2H, s); 2.92 (2H, d); 2.50 (3H, s); 1.94 (3H, s, br); 1.67 (3H, d); 1.59 (3H, d); 1.52 (6H, s).

c) 2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide.

A mixture 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 71b, 0.300 g) and ethanolamine (0.5 ml) in toluene (40 ml) was heated at 100° C. for 24 h. The mixture was cooled, poured into saturated aqueous sodium hydrogencarbonate solution, extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the subtitled compound as a gum (0.280 g).

MS (APCI+ve) MW 377/379 (M+H)+

d) [1-[[[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl](2-hydro xyethyl)amino]methyl]cyclopropyl]-carbamic acid, 1,1-dimethylethyl ester

2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3. 3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (0.250 g, Example 71c), (1-formylcyclopropyl)-carbamic acid, 1,1-dimethylethyl ester (0.260 g), sodium triacetoxyborohydride (0.600 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced to pressure. The crude material was purified on silica gel (ethyl acetate), to afford the subtitled compound (0.302 g).

MS (APCI+ve) MW 546/548 (M+H)+

e) 5-[[[(1-Aminocyclopropyl)methyl](2-hydroxyethyl)amino]methyl ]-2-chloro-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

[1-[[[[4-Chloro-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl](2-hydro xyethyl)amino]methyl]cyclopropyl]-carbamic acid, 1,1-dimethylethyl ester (Example 71d, 0.302 g) was dissolved in methanol (10 ml) and 4N HCl in dioxane (10 ml) was added. The mixture was stirred for 14 h at room temperature, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica (eluting with 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as an oil (0.230 g).

MS (APCI+ve) MW 446/448 (M+H)+

¹ H NMR (CDCl ₃ ) δ 7.69 (1H, s); 7.37 (2H, m); 6.38 (1H, t, br); 3.73 (2H, s); 3.64 (2H, t); 3.18 (2H, d); 2.74 (2H, t); 2.49 (2H, s); 2.21 (3H, s, br); 2.01 (3H, s, br); 1.75–1.64 (6H, m); 1.59 (6H, s, br); 0.59 (2H, t); 0.40 (2H, t).

EXAMPLE 72

5-[[(2-Hydroxyethyl)[2-(methylamino)ethyl]amino]methyl]- 2-methyl-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

a) [2-[(2-Hydroxyethyl)[[4-methyl-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]methylamino]ethy l]methyl-carbamic acid, 1,1-dimethylethyl ester

2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3. 3.1.1 ^3,7 )dec-1-ylmethyl)-benzamide (0.30 g, Example 71c), methyl(2-oxoethyl)-carbamic acid, 1,1-dimethylethyl ester (0.276 g), sodium triacetoxyborohydride (0.720 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica (eluting with 19:1 dichloromethane/methanol) to afford the subtitled compound (0.285 g).

MS (APCI+ve) MW 534/536 (M+H)+

b) 5-[[(2-Hydroxyethyl)[2-(methylamino)ethyl]amino]methyl]-2-me thyl-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide

[2-[(2-Hydroxyethyl)[[4 methyl-3-[[(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]eth yl]methyl-carbamic acid, 1,1-dimethylethyl ester (Example 72a, 0.285 g) was dissolved in methanol (10 ml), 4N HCl in dioxane (10 ml) was added and the mixture stirred for 14 h at room temperature. The solution was poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by chromatography over silica gel (eluting with 8:2:0.2/dichloromethane:methanol: ammonia) to afford the title compound as an oil (0.167 g).

MS (APCI+ve) MW 434/436 (M+H)+

¹ H NMR (CDCl ₃ ) δ 7.65 (1H, s); 7.35 (2H, s); 6.41 (1H, t, br); 3.67 (2H, s); 3.57 (2H, t); 3.17 (2H, d); 2.68–2.61 (6H, m); 2.38 (3H, s); 2.01 (3H, s, br); 1.76–1.63 (6H, m); 1.60 (6H, s, br).

EXAMPLE 73

2-Chloro-5-[3-[[2-(1-methyl-1H-imidazol-4-yl)ethyl]amino ]propyl]-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 6e, 0.5 g) and 3-methylhistamine (0.22 g) according to the procedure described in Example 6f to afford the title compound (0.060 g).

MS (APCI+ve) 469/471 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 9.45–9.30 (2H, m); 9.02 (1H, s); 8.32 (1H, t); 7.55 (1H, s); 7.41 (1H, d); 7.28 (1H, d); 7.26 (1H, d); 3.82 (3H, s); 3.30–3.20 (2H, m); 3.15 (2H, t); 2.95–2.85 (4H, m); 2.70 (2H, t); 2.02–1.93 (5H, m); 1.63 (6H, q); 1.52 (6H, s).

EXAMPLE 74

2-Chloro-5-[3-[[2-(1H-imidazol-4-yl)ethyl]amino]propyl]- N-(tricyclo [3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo(3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg) and histamine according to the procedure described in Example 6f to afford the title compound.

MS (APCI+ve) 455/457 (M+H) ⁺

EXAMPLE 75

2-Chloro-5-[3-[[3-(1H-imidazol-1-yl)propyl]amino]propyl] -N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)benzamide

Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1 .1 ^3,7 ]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg,) and 1-(3-aminopropyl)imidazole according to the procedure described in Example 6f to afford the title compound.

MS (APCI+ve) 469/471 (M+H) ⁺

EXAMPLE 76

2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricycl o[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt

Sodium triacetoxyborohydride (4.10 g) was added to a solution of 2-chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 ^3,7 ]dec-1-ylmethyl)-benzamide (3.46 g, Example 14b) and 3-aminopropanol (1.73 ml) in dichloromethane (200 ml). After 24 h the crude reaction mixture was purified by flash chromatography (eluting with 5–20% methanol/dichloromethane+1% ammonia) and the hydrochloride salt precipitated from ether/methanol 19:1, to afford the title compound as a white solid (1.60 g).

MS (APCI+ve) 419/421 (M+H) ⁺

¹ H NMR (DMSO-d ₆ ) δ 8.67 (2H, s); 8.31 (1H, t); 7.41 (1H, d); 7.30–7.25 (2H, m); 4.74 (1H, t); 3.47 (2H, q); 2.95–2.85 (6H, m); 2.67 (2H, t); 2.00–1.84 (5H, m); 1.76 (2H, quin); 1.63 (6H, q); 1.52 (6H, s).

Pharmacological Analysis

Certain compounds such as benzoylbenzyl adenosine triphosphate (bbATP) are known to be agonists of the P2X ₇ receptor, effecting the formation of pores in the plasma membrane (Drug Development Research (1996), 37(3), p. 126). Consequently, when the receptor is activated using bbATP in the presence of ethidium bromide (a fluorescent DNA probe), an increase in the fluorescence of intracellular DNA-bound ethidium bromide is observed. The increase in fluorescence can be used as a measure of P2X ₇ receptor activation and therefore to quantify the effect of a compound on the P2X ₇ receptor.

In this manner, each of the title compounds of the Examples was tested for antagonist activity at the P2X ₇ receptor. Thus, the test was performed in 96-well flat bottomed microtitre plates, the wells being filled with 250 μl of test solution comprising 200 μl of a suspension of THP-1 cells (2.5×10 ⁶ cells/ml) containing 10 ⁻⁴ M ethidium bromide, 25 μl of a high potassium buffer solution containing 10 ⁻⁵ M bbATP, and 25 μl of the high potassium buffer solution containing 3×10 ⁻⁵ M test compound. The plate was covered with a plastics sheet and incubated at 37° C. for one hour. The plate was then read in a Perkin-Elmer fluorescent plate reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X ₇ receptor agonist) and pyridoxal 5-phosphate (a P2X ₇ receptor antagonist) were used separately in the test as controls. From the readings obtained, a pIC ₅₀ figure was calculated for each test compound, this figure being the negative logarithm of the concentration of test compound necessary to reduce the bbATP agonist activity by 50%. Each of the compounds of the Examples demonstrated antagonist activity, having a pIC ₅₀ figure >5.0.